Kinase inhibitor scaffolds and methods for their preparation

ABSTRACT

General methods for the solution phase as well as solid phase synthesis of various substituted heteroaryls has been demonstrated. These substituted heteroaryls can be further elaborated by aromatic substitution with amines at elevated temperature or by anilines, boronic acids and phenols via palladium catalyzed cross-coupling reactions.

CROSS-REFERENCES TO RELATED APPLICATIONS

This patent application claims the benefit of U.S. Provisional PatentApplication No. 60/328,763, filed Oct. 12, 2001, U.S. Provisional PatentApplication No. 60/331,835, filed Nov. 20, 2001, U.S. Provisional PatentApplication No. 60/346,480, filed Jan. 7, 2002 and U.S. ProvisionalPatent Application No. 60/348,089, filed Jan. 10, 2002, the teachings ofall of which are incorporated herein by reference. This patentapplication is related to U.S. Provisional Patent Application No.60/328,741, filed Oct. 12, 2001, U.S. Provisional Patent Application No.60/346,552, filed Jan. 7, 2002, U.S. Provisional Patent Application No.60/347,037, filed Jan. 8, 2002, the teachings of all of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

With the large number of novel proteins being derived from genomics,proteomics, and traditional biochemical approaches there is a tremendousneed to develop more efficient methods for the discovery andoptimization of small molecule ligands to help determine the biologicalfunction of these proteins. Not surprisingly, many of these new targetscome from protein families that have received considerable attention((a) Dolle, R. E., Molecular Diversity, 3, 199 (1998); (b) Dolle et al.,J. Comb. Chem., 1, 235 (1999); (c) Dolle, R. E., J. Comb. Chem., 2, 383(2000) and references therein) in the past such as GPCRs, proteases, andkinases. This presents the combinatorial chemists with the opportunityto take scaffolds developed against a particular protein family memberand develop generalized synthetic schemes that allow other familymembers to be selectively targeted.

A survey of the literature (McMahon et al., Current Opinion in DrugDiscovery & Development, 1, 131 (1998); Adams et al., Current Opinion inDrug Discovery & Development, 2, 96 (1999); Garcia-Echeverria et al.,Med. Res. Rev, 20, 28 (2000) and references therein) reveals that thevast majority of kinase inhibitor scaffolds consist of planarheteroaryls that present both key hydrogen bond donating/acceptingfunctionality and proper hydrophobicity (FIG. 1).

The purine ring is a prime example of one of these planar heteroaryls.Guanosine and adenosine, two of the most common purines, serve as keyrecognition and anchoring elements in a variety of cofactors andsignaling molecules (e.g., ATP, GTP, cAMP, cGMP, adoMet, adenosine andNADH). Correspondingly, an enormous number of proteins have evolved torecognize the purine motif including reductases, polymerases,G-proteins, methyltransferases, and protein kinases. Despite theabundance of protein kinases (Venter, J. C. et al., Science, 291, 1304(2001)) (estimated to be encoded by 2 to 5% of the eukaryotic genome)and the high degree of conservation of active site residues, ATP-bindingsite directed inhibitors have been designed that are highly specific.For example, STI571 (Druker et al., Nat. Med., 2, 561 (1996); Zimmermannet al., Bioorg. Med. Chem. Lett., 7, 187 (1997); Schindler et al.,Science, 289, 1938 (2000)) has been developed as a potent and selectiveAb1 kinase inhibitor, and is in use for the treatment of chronicmyelogenous leukemia (CML). Screens of purine libraries (Gray et al.,Science, 281, 533 (1998) and references therein; Rosania et al., Proc.Natl. Acad. Sci. USA, 96, 4797 (1999); Chang et al., Chemistry andBiology, 6, 361 (1999)) have resulted in the identification of diversepurines that inhibit mitosis, alter cellular morphology, and induceapoptosis. By constructing new purine derivatives, we hope to developinhibitors of different ATP-dependent proteins, which will be useful forelucidating function and potentially provide starting points for thedevelopment of new therapeutics.

Previous syntheses of purine libraries have relied onnucleophilic-aromatic substitution and alkylation chemistry toderivatize the 2-, 6- and 9-positions of the purine ring. One of theprimary limitations of this chemistry is the inability to access a largenumber of pharmacologically relevant derivatives bearing aryl, anilinoor phenolic substituents. In addition, the sluggish aromaticsubstitution of 2-fluoro or 2-chloro substituted purine compoundsprecludes the introduction of sterically hindered amines or anilines(Chang et al., Chemistry and Biology, 6, 361 (1999)).

Recently, there have been significant advances in methodology forperforming palladium-catalyzed C—C, C—N and C—O bond formation reactionswith a wide variety of substrates. For example, new phosphine ligands(Wolfe et al., J. Am. Chem. Soc., 121, 9550 (1999); Stürmer, R., Angew.Chem. Int. Ed., 38, 3307 (1999) and references therein; Wolfe et al., J.Org. Chem., 65, 1158 (2000)) have allowed palladium mediatedfunctionalization of inexpensive chloroarenes with boronic acids andamines at room temperature. 1,3-Dimesityl-imidazolin-2-ylidene and itssaturated analog, originally developed by Grubbs as carbene ligands forruthenium-based olefin metathesis catalysts (Scholl et al., TetrahedronLett., 40, 2247 (1999); Scholl et al., Org. Lett., 1, 953 12 (1999)),have also been found to be highly effective ligands.

In view of the above, a method using transition metal-catalyzed couplingreaction for the preparation of substituted purines, as well as otherplanar heteroaryls, would provide access to a greater diversity ofsubstituted planar heteroaryls. Application of this method for thepreparation of libraries of planar heteroaryls, which is based on acombinatorial scaffold approach, would represent a significant advancein the art. Surprisingly, the present invention provides such a methodand compounds produced by the method.

BRIEF SUMMARY OF THE INVENTION

The present invention provides, inter alia, methods for the preparationof heteroaryls using both solution phase and solid phase chemistry. Themethods of the present invention are useful for the preparation of awide array of kinase inhibitor scaffolds and kinase inhibitors. Both thesolution and solid phase synthesis methodologies of the present methodprovides scaffolds and inhibitors, which are synthesized rapidly andwhich are substantially free of side products. In particular, themethods of the present invention are useful for preparingkinase-directed heteroaryl libraries using a combinatorial scaffoldapproach.

In addition to the method for preparing kinase inhibitor scaffolds andkinase inhibitors and, in particular, combinatorial libraries of suchkinase inhibitors, the present invention provides kinase inhibitorscaffolds and kinase inhibitors and, in particular, arrays or librariesof kinase inhibitors that are based on diverse planar heteroarylalkyland heteroaryl core molecules having pendant substituents.Representative core molecules include, but are not limited to, bothsubstituted and unsubstituted purines, pyrimidines, quinazolines,pyrazines, pyridazines, quinoxalines, phthalazines and thiadiazoles.Other appropriate planar heteroaryl scaffold components will be bothapparent, and readily accessible to those of skill in the art.

The scaffolds and inhibitors of the invention are prepared by anunexpectedly efficient process for adding elements of diversity to ascaffold element using solution phase as well as solid phase syntheticmethodologies.

Other objects and advantages of the present invention will be apparentfrom the detailed description and examples that follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 displays diverse kinase inhibitor scaffolds.

FIG. 2 displays examples of diverse heteroaryls constructed bycombinatorial scaffold approach of the invention.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

Definitions

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Generally,the nomenclature used herein and the laboratory procedures for organicand analytical chemistry are those well known and commonly employed inthe art.

As used herein, the term “leaving group” refers to a portion of asubstrate that is cleaved from the substrate in a reaction.

“Protecting group,” as used herein refers to a portion of a substratethat is substantially stable under a particular reaction condition, butwhich is cleaved from the substrate under a different reactioncondition. A protecting group can also be selected such that itparticipates in the direct oxidation of the aromatic ring component ofthe compounds of the invention. For examples of useful protectinggroups, see, for example, Greene et al., Protective Groups in OrganicSynthesis, John Wiley & Sons, New York (1991).

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). Examples of saturated hydrocarbon radicalsinclude groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl,cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group isone having one or more double bonds or triple bonds. Examples ofunsaturated alkyl groups include vinyl, 2-propenyl, crotyl,2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs andisomers. The term “alkyl,” unless otherwise noted, is also meant toinclude those derivatives of alkyl defined in more detail below as“heteroalkyl.” Alkyl groups which are limited to hydrocarbon groups aretermed “homoalkyl”.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and from one to three heteroatoms selectedfrom the group consisting of O, N, Si and S, and wherein the nitrogenand sulfur atoms may optionally be oxidized and the nitrogen heteroatommay optionally be quaternized. The heteroatom(s) O, N and S may beplaced at any interior position of the heteroalkyl group. The heteroatomSi may be placed at any position of the heteroalkyl group, including theposition at which the alkyl group is attached to the remainder of themolecule. Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Similarly, the term“heteroalkylene” by itself or as part of another substituent means adivalent radical derived from heteroalkyl, as exemplified by—CH₂—CH₂—S—CH₂CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl,3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkylinclude 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. In thespecific embodiments described herein, a particular halogen (e.g.,chloro) is sometimes specified. However, one of skill in the art couldsubstitute a different halogen for the one exemplified.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon substituent, which can be a single ringor multiple rings (up to three rings), which are fused together orlinked covalently. The term “heteroaryl” refers to aryl groups (orrings) that contain from zero to four heteroatoms selected from N, O,and S, wherein the nitrogen and sulfur atoms are optionally oxidized,and the nitrogen atom(s) are optionally quaternized. A heteroaryl groupcan be attached to the remainder of the molecule through a heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl,1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl,4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) is meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂ in a number ranging from zero to (2m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″, R′″ and R″″ eachpreferably independently refer to hydrogen, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, e.g., aryl substitutedwith 1-3 halogens, substituted or unsubstituted alkyl, alkoxy orthioalkoxy groups, or arylalkyl groups. When a compound of the inventionincludes more than one R group, for example, each of the R groups isindependently selected as are each R′, R″, R′″ and R″″ groups when morethan one of these groups is present. When R′ and R″ are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include,but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the abovediscussion of substituents, one of skill in the art will understand thatthe term “alkyl” is meant to include groups including carbon atoms boundto groups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: halogen, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″,—SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl,in a number ranging from zero to the total number of open valences onthe aromatic ring system; and where R′, R″, R′″ and R″″ are preferablyindependently selected from hydrogen, (C₁-C₈)alkyl and heteroalkyl,unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C₁-C₄)alkyl,and (unsubstituted aryl)oxy-(C₁-C₄)alkyl. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″ and R″″ groupswhen more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—,—CRR′— or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X—(CR″R′″)_(d)—, where s and d are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituents R, R′, R″ and R′″ are preferably independently selectedfrom hydrogen or substituted or unsubstituted (C₁-C₆)alkyl.

As used herein, the term “heterocycle,” refers to both heterocycloalkyland heteroaryl groups.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge et al., Journal of Pharmaceutical Science,66, 1-19 (1977)). Certain specific compounds of the present inventioncontain both basic and acidic functionalities that allow the compoundsto be converted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentinvention.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the present invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

The Compounds

In a first aspect, the present invention provides a compound having astructure selected from the following:

In the Formulae displayed immediately above, R₀ is a functional groupincluding, but not limited to, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl and acyl groups. R₁ is afunctional group including, but not limited to, substituted orunsubstituted alkyl and substituted or unsubstituted heteroalkyl. R₂ isa functional group including, but not limited to, substituted orunsubstituted planar heterocyclic or heteroaryl moiety. R₃, R₄ and R₅are independently selected and are functional groups including, but notlimited to, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocycloalkyl, halogens, and alkoxy groups.

In one embodiment, the present invention provides a compound having thefollowing formula:

In Formula XV, R is a functional group including, but not limited to, a5- or 6-membered heteroaryl and a 9- or 10-membered 6,5- or 6,6-fusedheteroaryl, containing from 1-4 nitrogen atoms, optionally substitutedwith 1-2 functional groups that are independently selected and include,but are not limited to, hydrogen, C₁₋₆alkyl, aryl, C₁₋₆alkylaryl,C₃₋₈cycloalkyl, heterocycle, heteroaryl, C₁₋₆alkylhydroxy, C₁₋₆alkoxyand NR⁴R⁴.

In a preferred embodiment, R is a 6-membered aromatic ring containing 2nitrogen atoms. In another preferred embodiment, R is a 6,5-fusedaromatic ring containing from 1-4 nitrogen atoms. In yet anotherpreferred embodiment, R is a 6,6-fused aromatic ring containing from 1-4nitrogen atoms.

In another embodiment, R is a functional group including, but notlimited to, the following:

In still another preferred embodiment, R is a functional groupincluding, but not limited to, the following:

In yet another preferred embodiment, R is a functional group including,but not limited to, the following:

In a presently preferred embodiment, the present invention provides acompound wherein R is the following structure:

In another embodiment, the present invention provides a compound whereinR is a 2,6,9-substituted purine, substituted with a functional groupincluding, but not limited to, the following:

In Formula XV, R¹ is a functional group including, but not limited to,phenyl and benzyl, substituted on the aromatic ring with from 1-4substituents that are independently selected and that include, but arenot limited to, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylhydroxy, C₁₋₆alkylamine,C₁₋₆aminoalkyl, halo and heterocycle. In a preferred embodiment, R¹ is aphenyl substituted with a morpholino group.

L, in Formula XV, is a functional group including, but not limited to,—O—, —NR²— and a bond. In a presently preferred embodiment, L is —O—.

In Formula XV, each R² is independently selected and is a functionalgroup including, but not limited to, hydrogen and C₁₋₄alkyl. In apreferred embodiment, R² is hydrogen or methyl.

R³, in Formula XV, is a functional group including, but not limited to,hydrogen, optionally substituted alkyl, optionally substitutedheteroalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocycloalkyl, halogen and alkoxygroups.

In an alternative embodiment, R² and R³ can be taken together to form a3-8 membered heterocyclic ring containing from 1-2 heteroatoms that areindependently selected from N and O, and that are optionally substitutedwith 1-2 substitutents that are independently selected and include, butare not limited to C₁₋₄alkyl, C₁₋₄alkylhydroxy, C₁₋₄alkoxy andC₁₋₄alkylamine.

R⁴, if present in Formula XV, is a functional group including, but notlimited to, optionally substituted alkyl, optionally substitutedheteroalkyl and acyl groups.

In a preferred embodiment, the present invention provides a compoundwherein R is a 2,6,9-substituted purine, substituted with a memberselected from the group consisting of:

R¹ is a phenyl substituted with morpholine, i.e., a morpholino group;

L-R³ is a member selected from the group consisting of:

R⁴ is not present or, if present, R⁴ is isopropyl.

Illustrative compounds of the present invention include, but are notlimited to, the following:

In a preferred embodiment, the present invention provides the followingcompounds:

The compounds of the present invention can exist as geometric isomers,most notably when olefins (carbon-carbon double bonds) are incorporated.The invention includes the individual geometric isomers as well asmixtures of isomers. When an asymmetric center is incorporated in acompound of the present invention, it can exist as a pair of opticalisomers. The invention includes the individual optical isomers as wellas mixtures thereof. When a compound of the present invention containsmultiple asymmetric centers, multiple centers of geometric isomerism,one or more centers of geometric isomerism in addition to one or moreasymmetric centers, the invention includes all combinations of geometricand optical isomers.

The compounds of the present invention can exist as neutral compounds oras acid addition salts. The invention includes both the neutral and saltforms. It specifically contemplates pharmaceutically acceptable acidaddition salts, including salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, andthe like, and salts formed with organic acids such as acetic acid,citric acid, fumaric acid, maleic acid, benzoic acid, methanesulfonicacid, and the like. The invention encompasses hydrated forms andsolvated forms of the compounds of the present invention and of theiracid addition salts.

Where a carboxylic acid is included, the compounds of the presentinvention can exist as neutral compounds or as salts, where thecarboxylate anion in paired with an organic or inorganic counterion. Thecounterion can be an external cationic species, or it can be an ammoniumgroup present within the compounds of the present invention, in whichcase the molecule is zwitterionic. The invention includes the neutraland salt forms, including zwitterionic forms. It specificallycontemplates pharmaceutically acceptable salts, including salts formedwith inorganic counterions such as lithium, sodium, potassium, ammonium,and the like, and salts formed with organic counterions, such asalkylammonium, dialkylammonium, trialkylammonium, tetralkylammonium,trialkylsulfonium, tetraalkyl or tetraaryl phosphonium counterions andthe like. The invention encompasses hydrated forms and solvated forms ofthe compounds of the present invention and of their carboxylate saltswhen a carboxylic acid group is present.

The compounds of the present invention can be readily screened for theirkinase inhibitory activity, i.e., their ability to inhibit kinases,using in vitro and in vivo assays known to those of skill in the art.For instance, purine analogs having protein kinase inhibitory activitycan be screened for using the CDK2/CYCLIN A microtiter-basedsolution-phase protein kinase assay described by Buxbaum, J. D., et a.l,Anal. Biochem,. 169:209-215 (1988), the teachings of which areincorporated herein by reference.

Methods

The present invention provides, inter alia, methods for the solutionphase and solid phase synthesis of substituted heteroaryls and, inparticular, substituted purines. In particular, the present inventionprovides methods for the solution phase synthesis of substitutedheteroaryls (such as substituted purines) as well as methods for thesolid phase synthesis of substituted heteroaryl scaffold moieties (suchas substituted purine moieties). The present invention further providemethods for the preparation of a chemical library or array ofsubstituted heteroaryl scaffold moieties through the application ofsolid-support media.

a) Solution Phase Synthesis of Substituted Heteroaryls (e.g.,Substituted Purines)

In one aspect, the present invention provides a method of preparing aC2-substituted purine compound, the method comprising: reacting aC2-halogenated purine compound with a compound of Formula I:A-X   Iin the presence of a solvent, a base, a carbene or phosphine ligand anda palladium catalyst to provide the C2-substituted purine compound. InFormula I, A is a functional group including, but not limited to, alkyl,substituted alkyl, aryl, substituted aryl, heterocyclyl and substitutedheterocyclyl; and X is a functional group including, but not limited to,—B(OH)₂, —OH, and —NHR¹, wherein R¹ is a functional group including, butnot limited to, hydrogen, alkyl and substituted alkyl.

In a preferred embodiment the C2-substituted purine compound is acompound of Formula II:

In Formula II, R² is a functional group including, but not limited to,hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyland substituted heterocyclyl;

X′, in Formula II, is a functional group including, but not limited to,a bond, NR¹ and O, wherein R¹ is as defined above.

X″, in Formula II, is a functional group including, but not limited to,a bond, O and NR³, wherein R³ is a functional group including, but notlimited to, hydrogen, alkyl and substituted alkyl, with the provisosthat when X″ is NR³, Y is R⁴ or A′, and that when X′ is O or a directbond, Y is A′.

In Formula II, A is as defined above, whereas A′ is a functional groupincluding, but not limited to, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl andsubstituted heterocyclyl.

If Y is R⁴, R⁴ is a functional group including, but not limited to,alkyl or substituted alkyl.

In a preferred embodiment, the C2-halogenated purine is a compoundhaving the structure of Formula III:

In Formula III, W is a halogen, i.e., a halo group, including, but notlimited to cholor, fluoro, bromo and iodo. In a presently preferredembodiment, W is a chloro or fluoro group. In Formula III, X″, Y and R²are as defined above. In a presently preferred embodiment, W is chloro;R² is isopropyl; X″ is NR³, wherein R³ is hydrogen; and A′ ismethoxybenzyl.

In one preferred embodiment, the present invention provides a method ofpreparing a C2-substituted purine compound of Formula II:

the method comprising: reacting a C2-halogenated purine compound ofFormula III:

with a compound of Formula I:A-X   I,in the presence of a solvent, a base, a carbene or phosphine ligand anda palladium catalyst, thereby forming the compound of Formula II.

In the compounds of Formulae I, II and III of the above method, W, X,X′X″, A, A′, Y, R¹, R², R³, R⁴ are as defined above.

In the above methods, carbene or phosphine ligands can be used. Examplesof ligands suitable for use in the methods of the present inventioninclude, but are not limited to, the following carbene and phosphineligands:

In a presently preferred embodiment, the ligand is a carbene ligandincluding, but not limited to, the following:

A number of bases can be used in carrying out the methods of the presentinvention. Examples of bases suitable for use in the above methodinclude, but are not limited to, cesium carbonate, potassium carbonate,sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesiumbicarbonate, potassium fluoride, potassium phosphate, potassiumtert-butyloxide, sodium tert-butyloxide, and triethylamine.

A number of solvents can be used in carrying out the methods of thepresent invention. Examples of solvents suitable for use in the abovemethod include, but are not limited to, 1,4-dioxane, tetrahydrofliran,dimethoxyethane (DME), dimethylformamide (DMF), benzene and toluene.

A number of palladium catalysts can be used in carrying out the methodsof the present invention. Typically, the oxidation state of thepalladium in the catalyst is (0) or (II). Examples of palladiumcatalysts suitable for use in carrying out the methods of the presentinvention include, but are not limited to, Pd₂(dba)₃, Pd(OAc)₂,Pd(PPh₃)₄, Pd(O), PdCl₂(dppf) and PdCl₂. Such catalysts are known to andused by those of skill in the art and, thus, their structures are known.In a preferred embodiment, the palladium catalyst is Pd₂(dba)₃.

In another embodiment, the present invention provides a method forpreparing a compound of Formula III, the method comprising: reacting adihalopurine, such as the compound of Formula IV:

with a compound of Formula V:X′″-A′  V,in the presence of a solvent, a base, a carbene or phosphine ligand anda palladium catalyst, thereby forming the compound of Formula III.

In the above method, W and W′ are both halogen; X′″ is a functionalgroup including, but not limited to, —B(OH)₂, —OH and NHR³, wherein R³is a functional group including, but not limited to, hydrogen, alkyl andsubstituted alkyl. In a preferred embodiment, W and W′ are both chloroor both fluoro.

In a preferred embodiment, the present invention provides a chemicallibrary comprising a plurality of 2-substituted purine compoundsprepared by the methods described above.

In another aspect, the present invention provides a method for preparinga C6-substituted purine compound, the method comprising: reacting aC6-halogenated purine with a compound of Formula I:A-X   I,in the presence of a solvent, a base, a carbene or phosphine ligand anda palladium catalyst to provide the C6-substituted purine compound. InFormula I, A is a functional group including, but not limited to, alkyl,substituted alkyl, aryl, substituted aryl, heterocyclyl and substitutedheterocyclyl; and X is a functional group including, but not limited to,—B(OH)₂, —OH, and —NHR¹, wherein R¹ is a functional group including, butnot limited to, hydrogen, alkyl and substituted alkyl.

In a preferred embodiment the C6-substituted purine compound is acompound of of Formula VI or Formula VII:

In Formula VI, R² is a functional group including, but not limited to,hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyland substituted heterocyclyl.

X′, in Formula VI, is a functional group including, but not limited to,a bond, NR¹ and O, wherein R¹ is a functional group including, but notlimited to, hydrogen, alkyl and substituted alkyl.

X″, in Formula VI, is a functional group including, but not limited to,a bond, O and NR³, wherein R³ is a functional group including, but notlimited to, hydrogen, alkyl and substituted alkyl, with the proviso thatwhen X″ is NR³, Y is R⁴ or A′, and when X is O or a direct bond, Y isA′.

In Formula VI, A is a functional group including, but not limited to,alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl andsubstituted heterocyclyl, whereas A′ is a functional group including,but not limited to, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heterocyclyl and substitutedheterocyclyl;

R⁴, in Formula VI, is a functional group including, but not limited to,alkyl or substituted alkyl.

In a presently preferred embodiment, the C6-halogenated purine is acompound of Formula VII:

In Formula VII, W is a halogen or halo group (e.g., chloro, fluoro,bromo or iodo), whereas X′ and Y are as defined above.

In another aspect, the present invention provides a method for preparinga C6-substituted purine compound of Formula VI:

the method comprising: reacting a C6-halogenated purine of Formula VII:

with a compound of Formula I:A-X   I,in the presence of a solvent, a base, a carbene ligand and a palladiumcatalyst to provide a C6-substituted purine compound of Formula VI.

In a presently preferred embodiment, the present invention provides achemical library comprising a plurality of 6-substituted purinecompounds prepared by the methods described above.

It is noted that the discussion (as well as preferred embodiments)relating to the carbene or phophine ligands, bases, solvents andpalladium catalysts set forth in connection with the method forpreparing a C-2 substituted purine compound are fully applicable to themethod for preparing a C-6 substituted purine compound and, thus, itwill not be repeated here.

In yet another embodiment, the present invention provides a method forpreparing a 9-aryl substituted purine compound, the method comprising:reacting a 2,6-dihalogenated purine with a compound of Formula X:Ar—B(OH)₂   X,in the presence of a solvent and a catalyst, to provide the 9-arylsubstituted purine compound.

In Formula X, Ar is a functional group including, but not limited to,aryl, substituted aryl, heterocyclyl and substituted heterocyclyl.

In a presently preferred embodiment, the 9-aryl substituted purinecompound is a compound of Formula IX:

In Formula IX, Ar is a functional group including, but not limited to,aryl, substituted aryl, heterocyclyl and substituted heterocyclyl. W andW′, in Formula IX, are each independently selected and include, but arenot limited to, fluoro, chloro, bromo and iodo.

In a preferred embodiment of the foregoing method, the catalyst is acopper catalyst. Suitable copper catalysts for use in the presentinvention will be known to and used by those of skill in the art.Typically, the copper of the copper catalyst is in an oxidation state of(0), (I) or (II). Examples of copper catalysts suitable for use in themethod of the present invention include, but are not limited to,Cu(OAc)₂, [Cu(OH)●TMEDA]₂Cl₂ and CuI. In a presently preferredembodiment, the catalyst is cupric acetate.

A number of solvents can be used in carrying out the methods of thepresent invention. Examples of solvents suitable for use in the abovemethod include, but are not limited to, 1,4-dioxane, tetrahydrofuran,dimethoxyethane (DME), dimethylformamide (DMF), benzene and toluene.

In a presently preferred embodiment, the present invention provides achemical library comprising a plurality of 9-aryl substituted purinecompounds prepared by the methods described above.

b) Solid Phase Synthesis of Substituted Heteroaryls (e.g., SubstitutedPurines)

In yet another aspect, the present invention provides a method forsynthesizing a substituted heteroaryl, the method comprising: (a)providing a dihaloheteroaryl scaffold moiety; and (b) capturing thedihaloheteroaryl scaffold moiety on a resin by nucleophilic substitutionof a first halogen by a resin-bound amine nucleophile to afford asubstituted heteroaryl, e.g, a resin-bound amine substitutedmonohaloheteroaryl.

Suitable resins useful for the present invention include, but are notlimited to, PAL resin, Wang resin, and polystyrene resin. Other suitableresins would be clear to a person of skill in the art. In a preferredembodiment, the PAL resin is utilized.

In a preferred embodiment, the two halogens, i.e., halo groups, of thedihaloheteroaryl scaffold moiety are independently selected and include,but are not limited to, chloro, fluoro, bromo and iodo. In a presentlypreferred emodiments, the two halogens are chloro or fluoro groups.

In a preferred embodiment, the method further comprises substitution ofthe second halogen of the dihaloheteroaryl scaffold moiety bynucleophilic displacement or, alternatively, by a coupling reaction.In-a presently preferred embodiment, a coupling reaction is employed tocarry out the substitution of the second halogen of the dihaloheteroarylscaffold moiety. In this connection, the coupling reaction is preferablya palladium-mediated coupling reaction.

It will be readily apparent to those of skill in the art that the twohalogens, i.e., halo groups, of the dihaloheteroaryl scaffold moiety canbe substituted with a number of different functional groups. Suitablefunctional groups include, but are not limited to, anilines, phenols,amines and boronic acids (see, Table 1). In a preferred embodiment, thefunctional group includes, but is not limited to, aryl boronic acids,anilines and phenols.

In a preferred embodiment, the method further comprises performing aninitial substitution prior to substitution of the first halogen of thedihaloheteroaryl scaffold moiety. In a preferred embodiment, the initialsubstitution is carried out using a reaction including, but not limitedto, alkylation reactions, acylation reactions and coupling reactions.

Numerous dihaloheteroaryl scaffold moieties can be used in the methodsof the present invention. Examples of suitable dihaloheteroaryl scaffoldmoieties include, but not limited to, purines, pyrimidines,quinazolines, pyrazines, phthalazines, pyradazines and quinoxalines.

When a palladium-catalyzed coupling reaction is employed to substitutethe halo groups of the dihaloheteroary or the halo group of theresin-bound amine substituted monohaloheteroaryl, thepalladium-catalyzed coupling reaction typically involves reacting thedihaloheteroaryl or the resin-bound amine substituted monohaloheteroarylwith a coupling agent in the presence of a solvent, a palladiumcatalyst, a base and a carbene or phosphine ligand. Suitable couplingagents include, but are not limited to, boronic acids, amines andalcohols. In a presently preferred embodiment, suitable coupling agentsinclude, but are not limited to, aryl boronic acids, anilines andphenols. It is noted that the foregiong discussions relating to thecarbene or phophine ligands, bases, solvents, palladium catalysts andcopper catalysts set forth in connection with the methods for preparinga C-2 substituted purine compound or a 9-aryl substituted purinecompound are fully applicable to the method for preparing a substitutedheteroaryl compound and, thus, they will not be repeated here.

In a preferred embodiment, the foregoing methods further comprisecleaving the compound from the solid support. It will be readilyappreciated that the compounds of the present invention can be readilycleaved from the solid support using standard methods known to and usedby those of skill in the art. Cleavage of a resin-bound compound ndliberation of the desired compound from the resin is typically carriedin the presence of an acid. Suitable acids include, but are not limitedto, an organic acid such as formic acid, acetic acid, propionic acid,trichloroacetic acid, trifluoroacetic acid and the like, and inorganicacids such as hydrochloric acid, hydrobromic acid, sulfuric acid,hydrogen chloride, etc., or the like. The reaction is usually carriedout in a solvent such as water, an alcohol such as methanol, ethanol,1,4, dioxane, methylene chloride, tetrahydrofuran, a mixture thereof orany other solvent which does not adversely influence the reaction.

In yet another aspect of the present invention, the foregoing method isadapted to prepare a library (or an array) of heteroaryl scaffoldmoieties. Typically, the library of substituted scaffold moieties isprepared using a plurality of dihaloheteroaryl scaffold moieties. Assuch, in another aspect, the present invention provides a method forsynthesizing a combinatorial library of substituted heteroaryls (e.g.,heterocycles), the method comprising: providing a plurality ofdihaloheterocyclic scaffold moieties; and capturing thedichloroheterocyclic scaffold moieties on a resin by nucleophilicsubstitution of a first chlorine by a resin-bound amine nucleophile).

In a preferred embodiment, the two halogens, i.e., halo groups, presentin the dihaloheteroaryl scaffold moieties are independently selected andinclude, but are not limited to, chloro, fluoro, bromo and iodo. In apresently preferred emodiments, the two halogens of the dihaloheteroaryscaffold moieites are chloro groups.

In a preferred embodiment, the method further comprises substitution ofthe second halogen of the dihaloheteroaryl scaffold moieties bynucleophilic displacement or, alternatively, by a coupling reaction. Ina presently preferred embodiment, a coupling reaction is employed tocarry out the substitution of the second halogen of the dihaloheteroarylscaffold moieties. In this connection, the coupling reaction ispreferably a palladium-mediated coupling reaction.

It will be readily apparent to those of skill in the art that the twohalogens, i.e., halo groups, of the dihaloheteroaryl scaffold moietiescan be substituted with a number of different functional groups, each ofwhich is independently selected. Suitable functional groups include, butare not limited to, anilines, phenols, amines and boronic acids (see,Table I). In a presently preferred embodiment, the functional groupsinclude, but are not limited to, aryl boronic acids, anilines andphenols.

In a preferred embodiment, the method further comprises performinginitial substitutions prior to substitution of the first halogens of thedihaloheteroaryl scaffold moieties. In a preferred embodiment, theinitial substitution is carried out using a reaction including, but notlimited to, alkylation reactions, acylation reactions and couplingreactions.

Numerous dihaloheteroaryl scaffold moieties can be used in the methodsof the present invention. Examples of suitable dihaloheteroaryl scaffoldmoieties include, but not limited to, purines, pyrimidines,quinazolines, pyrazines, phthalazines, pyradazines and quinoxalines.

When a palladium-catalyzed coupling reaction is employed to substitutethe halo groups of the dihaloheteroary scaffold moieties or the halogroup of the resin-bound amine substituted monohaloheteroaryls, thepalladium-catalyzed coupling reaction typically involves reacting thedihaloheteroaryl or the resin-bound amine substituted monohaloheteroarylwith a coupling agent in the presence of a solvent, a palladiumcatalyst, a base and a carbene or phosphine ligand. Suitable couplingagents include, but are not limited to, boronic acids, amines andalcohols. In a presently preferred embodiment, suitable coupling agentsinclude, but are not limited to, aryl boronic acids, anilines andphenols. It is noted that the foregiong discussions relating to thecarbene or phophine ligands, bases, solvents, palladium catalysts andcopper catalysts set forth in connection with the methods for preparinga C-2 substituted purine compound or a 9-aryl substituted purinecompound are fully applicable to the methods for preparing acombinatorial library or array of substituted heteroaryl compound and,thus, they will not be repeated here.

c) Illustrative Embodiments: Preparation of Libraries of HeteroarylScaffold Moieties via Solid Support Chemistry

An exemplary strategy for preparing the scaffolds and inhibitors of thepresent invention relies on the capture of a dichloroheterocyclicscaffold (including substituted purines S1, pyrimidines S2, quinazolinesS3, pyrazines S4, pyridazines S5, quinoxalines S6, phthalazines S7 andthiadiazoles S8) with a resin-bound amine nucleophile where one chlorogroup is susceptible to nucleophilic aromatic substitution. Depending onthe type of heterocycle being captured, an initial alkylation, acylationor coupling reaction can be performed prior to the capture step tointroduce one diversity element. The remaining chloro substituent isthen available for nucleophilic displacement or a palladium-mediatedcoupling reaction with anilines, phenols, and boronic acids.

In an exemplary embodiment, the scaffolds and inhibitors of theinvention are assembled using the procedure outlined in Scheme 1.

In an exemplary embodiment, the heterocycle capture strategy uses2,6-dichloropurine because the 6-chloro can be selectively displaced byamines and the 2-chloro has been demonstrated to function inpalladium-mediated coupling reactions in solution (see, U.S. ProvisionalApplication No. 60/328,763, entitled “Expanding the Diversity of PurineLibraries,” which was filed Oct. 12, 2001).

Suitable resins useful for the present invention would be clear to aperson of skill in the art. In a preferred embodiment, a resin-boundnucleophilic amino group can be obtained through the coupling of primaryamines to a (4-formyl-3,5-dimethoxyphenoxy)methyl-polystyrene resin(PAL-resin) by reductive amination using sodium triacetoxyborohydridewith 1% acetic acid to afford the PAL-amine resin) (see, Albericio etal., J. Org. Chem., 55, 3730 (1990); Boojamra et al., J. Org. Chem., 62,1240 (1997); and Jin et al., J. Comb. Chem., 3, 97 (2001)). The PALlinkage offers the advantage that functionalized amines can readily beinstalled and cleavage results in an NH group that serves as a keyhydrogen bond donor to many kinase active sites. A representativesequence starts by loading 2,6-dichloropurine onto the PAL-amine at themore reactive C6 position in butanol at 80° C. with exclusiveregioselectivity. Modification of the N9 position of purine can beachieved by either Mitsunobu alkylation of N9 on a solid support (PathB) or by capturing the product of a solution phase Mitsunobu alkylationof 2,6-dichloropurine (Path A, Scheme 2). The latter approach offers theadvantages of using less reagents and ease of handling. However,alkylation on a solid support provides improved regio-selectivity(N9/N7), presumably because N7 is more sterically hindered due to thepresence of a large substituent at C6. Having the flexibility to performthe alkylation either on a solid support or in solution offers differentoperational advantages when making large combinatorial libraries. Mostprimary and secondary alcohols lacking additional acidic hydrogens workwell in the Mitsunobu reaction at N9 (see, Chang et al., Chemistry andBiology, 6, 361 (1999); and U.S. Provisional Application No. 60/328,741,entitled “A Concise and Traceless Linker Strategy Toward CombinatorialLibraries of 2,6,9-Substituted Purines,” which was filed Oct. 12, 2001).

In another exemplary embodiment, a palladium-catalyzed cross-couplingstep can be performed as, for example, a final derivatization process,as illustrated in Scheme 2.

As illustrated in Scheme 2, a palladium-catalyzed cross-couplingreaction is performed as the final derivatization step. An exemplaryembodiment utilizes approximately five equivalents of the couplingpartner (arylboronic acids, anilines or phenols), 7 mol % of Pd₂(dba)₃,14 mol % of the corresponding ligand and six equivalents of the base.The resulting mixture is maintained for 12 hours at 80° C. with1,4-dioxane for C—C and C—N bond formation or toluene for C—O bondformation as solvent. Although the reaction time and the amount ofcoupling reagents can be optimized for each type of reaction andsubstrate, the general coupling protocol described above is generallyuseful for achieving quantitative conversion of the starting material(the chloro-group at the C2 position of purine) with differentsubstrates on the solid support.

The palladium catalyzed cross-coupling reaction can also be used toprepare heterocycloalkyl and heteroaryl moieties having an array ofsubstituents appended thereto. For example, resin-bound purine 3 (X═Cl,Y═H, Scheme 2) can be reacted with a variety of arylboronic acids,anilines/amines, and phenols. See, Table 1. Analysis of the productsfollowing TFA mediated cleavage by LC-MS revealed greater that 95%conversion with a variety of electron rich or poor aromatic ringsystems. The amination reaction proved to be the most versatile withdiverse substrates ranging from primary and secondary anilines to asterically hindered primary amine (2-amino-3-methyl-butanol) andcyclic/acyclic secondary amines (see Table 1). While all three types ofpalladium-catalyzed cross-coupling reactions on solid support werepreferentially carried out in concentrated form (>0.2M), the aminationreaction is preferably performed with at least 0.2 M aniline otherwise asignificant amount of t-butoxide substituted product can be observed.TABLE 1 Boronic Acids Anilines Amines Phenols

The palladium catalyzed C2-couplings on solid support can be extended tothe reaction to C-8 halo-substituted purines (e.g., C-8 bromo orchloro-substituted purines). In an exemplary embodiment, the C-8bromo/chloro substituted purines are prepared by lithiation of the C8position of 6-chloro-9-tetrahydropyranyl or2,6-dichloro-9-tetrahydropyranyl purine with LDA followed by quenchingwith appropriate halogen donors. The tetrahydropyranyl protecting groupcan be removed by treatment with 10% acetic acid in methanol. AfterMitsunobu alkylation of N9 and resin capture at C6, the support-boundpurines can be modified at C8 or C2 and C8 simultaneously usingpalladium-mediated cross-coupling reactions as described above (see,Scheme 2). This chemistry provides access to known adenosine-P1 receptorantagonists as well as generic 6-5-6 triaryl systems that represent alarge class of bioactive pharmacophores.

The heterocycle resin-capture strategy of the present invention hasbroad general applicability. For example, a collection ofdichloroheterocycles can be coupled to PAL-amine resin. The generalresin capture condition involves reacting 2 equivalents ofdichloroheterocycles with PAL-amine in the presence of 3 equivalents ofdiisopropylethylamine at 90° C. in butanol for 24 hours. Because theresin-capture presumably proceeds through a nucleophilic aromaticsubstitution mechanism, electron poor dichloroheterocycles are loaded onsolid support quantitatively using the reaction condition describedabove. These include all the heterocycles shown in Scheme 1.

According to the present invention certain heterocycles, such as2,4-dichloropyrimidine are captured at room temperature with highefficiency. The capture of other heterocycles is possible using themethods set forth herein. Different scaffolds can require differentconditions for efficient capture to occur. For example, S4 to S6 requiremore forcing conditions (90° C., n-butanol, 24 hrs., quantitativeloading) than 2,4-dichloropyrimidine. Determining suitable captureconditions for a particular heterocycloalkyl or heteroaryl group is wellwithin the abilities of those of skill in the art.

Using the methods set forth herein, it is possible to obtainregioselective capture of a scaffold. For example,2,4-dichloropyrimidine resulted in a regioisomeric mixture with someresin-bound amines, e.g., PAL-resin-bound primary amines capture2,4-dichloropyrimidine exclusively at C4 position. Thepalladium-catalyzed amination conditions provided herein can be used tocarry out resin-capture of less electron poor dichloroheterocycles withmoderate loading.

Following capture of the dichloroheterocycles on the solid support, theremaining chloro substituent is generally replaced by another group. Inone embodiment, the chloro group is replaced in a palladium-catalyzedcross-coupling reaction. In an exemplary embodiment, R₁ was fixed asp-methoxybenzylamine and the remaining chloro group of theresin-captured heterocyclic scaffolds was subjected to apalladium-catalyzed cross-coupling reaction as the final derivatizationstep. The reaction conditions are essentially the same as described forthe purines. These conditions are general for both modifying the wholespectrum of resin-captured heterocycles with all regioisomers andachieving quantitative conversion of the starting material (theremaining chloro-group) with different substrates on the solid support.While the yields of the cleaved final products mainly depend on thecapture step which can be achieved quantitatively using the standardizedcapture condition described above (since quantitative palladiumcatalyzed final derivatization can be easily achieved), littleimpurities sometimes appeared when the qualities of coupling substrates(boronic acids, anilines and phenols) varied. For example, up to 5% ofde-halogenation product could be observed when the substrates aresomewhat wet. Removal of small amounts of impurity is within theabilities of those of skill in the art by methods such asrecrystallization, chromatography, extraction and the like.

In some embodiments, it has been found that the use of resin-bound aminoalcohol, such as ethanolamine derivatives, results in intramolecularcyclization products under the palladium catalyzed C—C or C—O bondformation condition even with excess boronic acids or phenols aroundwhere the oxygen atom of the resin-bound amino alcohol displaces theproximal remaining chloro group of the heterocycle to form 6 or7-membered ring system.

In another exemplary embodiment, the chloro group is replaced usingnucleophilic aromatic substitution conditions. The less reactiveC2-chloro group of pyrimidine (S2), quinazoline (S3) and C3-chloro ofthiadiazole (S8) reacts with various amines quantitatively. Preferredconditions include high concentration (>2M) amine and reactions times ofabout 12 hours at 100° C.

In yet another exemplary embodiment, anilines react with the C2 chlorogroup of pyrimidine scaffold. Preferred conditions are 0.2M of theaniline at 80° C. The C6-chloro group of pyrimidine and the secondchloro group of scaffolds S4 through S7 can react quantitatively withanilines in the presence of a stoichiometric amount of potassiumt-butoxide as the base.

As only a small subset of the heterocycles could be modified understandard nucleophilic aromatic substitution conditions, the use ofpalladium-catalyzed cross-coupling reactions on solid support wasinvestigated. With R₁ fixed as p-methoxybenzylamine, the remainingchloro group of the resin-captured heterocyclic scaffolds was subjectedto a palladium-catalyzed cross coupling reaction as the finalderivatization step. The reaction conditions are essentially the same asdescribed for the purines. These conditions were found to be mostgeneral for modifying the resin-captured heterocycles (see, Table 2) andgenerally afforded quantitative conversion of the starting material (theremaining chloro group) with different substrates on the solid support.Exploration of the reaction scope revealed the same broad range ofsubstrates can be used as demonstrated for the purine scaffold (seeTable 1). A survey of resin-bound amines also showed considerablediversity in primary amines that are effective substrates. Onlyβ-branched resin-bound primary amines were found to have relatively slowcapture rates. Interestingly, the use of resin-bound amino alcohols,such as ethanolamine derivatives, can provide intramolecular cyclizationproducts for 2,3-dichloroquinoxaline and 2,3-dichloropyrazine under thepalladium-catalyzed C—C or C—O bond formation conditions to form six- orseven-membered ring systems (Torraca et. al., J. Am. Chem. Soc., 122,12907-12908) (2000) (Scheme 3). TABLE 2 Validation of HeterocyclicScaffolds as Diversity Inputs

(Y₁) (Y₂) (Y₃) Purity & Purity & Purity & Entry Scaffolds (R₂) Yield (%)Yield (%) Yield (%) 1

95 (90) 96 (90) 92 (86) 2

90 (91) 95 (91) 91 (85) 3

96 (91) 96 (90) 96 (88) 4

93 (89) 95 (90) 96 (88) 5

91 (85) 88 (82) 90 (83) 6

95 (90) 91 (89) 93 (89) 7

86 (79) 89 (78) 85 (78) 8

92 (85) 93 (86) 94 (85) 9

91 (82) 96 (89) 95 (89) 10

93 (83) 93 (85) 92 (88) 11

90 (80) 93 (86) 96 (88) 12

94 (84) 94 (80) 91 (84) 13

92 (80) 92 (84) 90 (83) 14

91 (84) 92 (87) 91 (88) 15

93 (84) 85 (81) 91 (83)

In summary, in this aspect, the invention provides a general method forthe solid synthesis of various substituted heterocycles. Alkylatedpurines halogenated at the 2,3 6,8 or 2,6,8 positions and variousdihaloheterocycles can be captured onto solid support and furtherelaborated by aromatic substitution with amines at elevated temperatureor by anilines, boronic acids, and phenols via palladium-catalyzedcross-coupling reactions.

The combinational scaffold approach described herein can be used inconjunction with one or more of the methods for making substitutedheterocycles (including purines) that are described in U.S. ProvisionalApplication No. 60/328,763, which is entitled “Expanding the Diversityof Purine Libraries,” and was filed on Oct. 12, 2001. The approach isalso suitable for use with the methods for making substitutedheterocycles described in U.S. Provisional Application No. 60/328,741,which is entitled “A Concise and Traceless Linker Strategy TowardCombinatorial Libraries of 2,6,9-Substituted Purines,” and was filed onOct. 12, 2001, and in U.S. Provisional Application Nos. 60/346,552 and60/347,037, entitled “Methods For the Synthesis of Substituted PurineLibraries,” which were filed on Jan. 7 and 8, 2002.

Pharmaceutical Formulations

In another preferred embodiment, the present invention provides apharmaceutical formulation comprising a compound of the invention and apharmaceutically acceptable carrier.

The compounds described herein, or pharmaceutically acceptable additionsalts or hydrates thereof, can be delivered to a patient using a widevariety of routes or modes of administration. Suitable routes ofadministration include, but are not limited to, inhalation, transdermal,oral, rectal, transmucosal, intestinal and parenteral administration,including intramuscular, subcutaneous and intravenous injections.

The compounds described herein, or pharmaceutically acceptable saltsand/or hydrates thereof, can be administered singly, in combination withother compounds of the invention, and/or in cocktails combined withother therapeutic agents. Of course, the choice of therapeutic agentsthat can be co-administered with the compounds of the invention willdepend, in part, on the condition being treated.

For example, when administered to a patient undergoing cancer treatment,the compounds can be administered in cocktails containing anti-canceragents and/or supplementary potentiating agents. The compounds can alsobe administered in cocktails containing agents that treat theside-effects of radiation therapy, such as anti-emetics, radiationprotectants, etc.

Supplementary potentiating agents that can be co-administered with thecompounds of the invention include, e.g., tricyclic anti-depressantdrugs (e.g., imipramine, desipramine, amitriptyline, clomipramine,trimipramine, doxepin, nortriptyline, protriptyline, amoxapine andmaprotiline); non-tricyclic and anti-depressant drugs (e.g., sertraline,trazodone and citalopram); Ca⁺² antagonists (e.g., verapamil,nifedipine, nitrendipine and caroverine); amphotericin; triparanolanalogues (e.g., tamoxifen); antiarrhythmic drugs (e.g., quinidine);antihypertensive drugs (e.g., reserpine); thiol depleters (e.g.,buthionine and sulfoximine); and calcium leucovorin.

The active compound(s) of the invention are administered per se or inthe form of a pharmaceutical composition wherein the active compound(s)is in admixture with one or more pharmaceutically acceptable carriers,excipients or diluents. Pharmaceutical compositions for use inaccordance with the present invention are typically formulated in aconventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries, which facilitateprocessing of the active compounds into preparations which, can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen.

For injection, the agents of the invention can be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks's solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants appropriate to the barrier to bepermeated are used in the formulation. Such penetrants are generallyknown in the art.

For oral administration, the compounds can be formulated readily bycombining the active compound(s) with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the compounds ofthe invention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained solid excipient, optionally grinding aresulting mixture, and processing the mixture of granules, after addingsuitable auxiliaries, if desired to obtain tablets or dragee cores.Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxyniethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents can beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations, which can be used orally, include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds can be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers can be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof such as sodium alginate.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances, which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents, which increase the solubility of thecompounds to allow for the preparation of highly, concentratedsolutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation or transcutaneous delivery (e.g.,subcutaneously or intramuscularly), intramuscular injection or atransdermal patch. Thus, for example, the compounds may be formulatedwith suitable polymeric or hydrophobic materials (e.g., as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

EXAMPLES

General Considerations. Purity of compounds were assessed byreverse-phase liquid chromatography—mass spectrometer (Agilent Series1100 LC-MS) with an UV detector at λ=255 nm (reference at 360 nm) and anAPI-ES ionization source. NMR spectra were recorded on Bruker-400 MHzand 500 MHz instrument and calibrated using residual undeuteratedsolvent as an internal reference. The following abbreviations were usedto designate the multiplicities: s=singlet, d=doublet, t=triplet,q=quartet, m=multiplet. LC elution methods (using a Phenomenex Luna50*2.00 mm 5μ C18 column): (1) 10 minutes method: starting from 5%solvent A (acetonitrile) in solvent B (water with 0.5% acetic acid) andrunning the gradient to 95% A in 8 minutes, followed by 2 minuteselution with 95% A. (2) 17 minutes method: starting from 5% solvent A(acetonitrile) in solvent B (water with 0.5% acetic acid) and runningthe gradient to 95% A in 15 minutes, followed by 2 minutes elution with95% A.

Example 1 General Procedure for the Solution Phase Svnthesis of2,6,9-substituted Purines

Boronic Acid coupling reactions: A 10 mL flame-dried Schlenk flaskequipped with a magnetic stir bar was charged with2-chloro-6-(4-methoxybenzylamino)-9-isopropylpurine (0.193 g, 0.5 mmol,1.0 equiv), 2,4-dimethoxyphenylboronic acid (0.136 g, 0.75 mmol, 1.5equiv), Pd₂(dba)₃ (0.0069 g, 0.0075 mmol, 0.015 equiv.), ligand 1(0.0051 g, 0.015 mmol, 0.03 equiv.) and Cs₂CO₃ (0.326 g, 1.0 mmol, 2.0equiv.). The Schlenk flask was evacuated and backfilled with argon andcharged with anhydrous 1,4-dioxane (2.0 mL). The reaction was stirredunder argon at 80° C. and monitored by TLC. When the reaction wascomplete after 8 hours, the solvent was removed in vacuo and thereaction crude was purified by flash column chromatography (3% methanolin dichloromethane) to afford desired2-(2,4-dimethoxyphenyl)-6-(4-methoxybenzylamino)-9-isopropylpurine (207mg, 96%). ¹H NMR (400 MHz, CDCl₃) δ 1.59 (d, 6H, J=6.8 Hz), 3.79 (s,3H), 3.84 (s, 3H), 3.85 (s, 3H), 4.87-4.96 (m, 3H), 6.14 (br, 1H),6.57-6.60 (m, 2H), 6.85 (d, 2H, J=8.6 Hz), 7.34 (d, 2H, J=8.6 Hz), 7.73(s, 1H), 7.78 (d, 1H, J=8.2 Hz); HRMS (MALDI-FTMS) [MH⁺]C₂₄H₂₈N₅O₃434.2187, found: 434.2168.

Aniline coupling: A 10 mL flame-dried Schlenk flask equipped with amagnetic stir bar was charged with2-chloro-6-(4-methoxybenzylamino)-9-isopropylpurine (0.193 g, 0.5 mmol,1.0 equiv), 4-methoxyaniline (0.092 g, 0.75 mmol, 1.5 equiv), Pd₂(dba)₃(0.0069 g, 0.0075 mmol, 0.015 equiv.), ligand 1 (0.0051 g, 0.015 mmol,0.03 equiv.) and KO^(t)Bu (0.112 g, 1.0 mmol, 2.0 equiv.). The Schlenkflask was evacuated and backfilled with argon and charged with anhydrous1,4-dioxane (2.0 mL). The reaction was stirred under argon at 80° C. andmonitored by TLC. When the reaction was complete after 8 hours, thesolvent was removed in vacuo and the reaction crude was purified byflash column chromatography (3% methanol in dichloromethane) to afforddesired2-(4-methoxyphenylamino)-6-(4-methoxybenzylamino)-9-isopropylpurine (203mg, 97%): ¹H NMR (500 MHz, CDCl₃) δ 1.54 (d, 6H, J=6.6 Hz), 3.76 (s,3H), 3.78 (s, 3H), 4.66 (m, 1H, J=6.6 Hz), 4.72 (br, 2H), 6.06 (br, 1H),6.60 (br, 1H), 6.82 (d, 2H, J=13 Hz), 6.84 (d, 2H, J=13 Hz), 7.09 (s,1H), 7.26 (d, 2H, J=8.8 Hz), 7.42 (s, 1H), 7.56 (d, 2H, J=8.8 Hz); HRMS(MALDI-FTMS) [MH⁺] C₂₃H₂₇N₆O₂ 419.2195, found: 419.2209.

Phenol coupling: A 10 mL flame-dried Schlenk flask equipped with amagnetic stir bar was charged with2-chloro-6-(4-methoxybenzylamino)-9-isopropylpurine (0.193 g, 0.5 mmol,1.0 equiv), 4-methylphenol (0.081 g, 0.75 mmol, 1.5 equiv), Pd₂(dba)₃(0.0069 g, 0.0075 mmol, 0.015 equiv.), ligand 1 (0.0051 g, 0.015 mmol,0.03 equiv.) and KO^(t)Bu (0.112 g, 1.0 mmol, 2.0 equiv.). The Schlenkflask was evacuated and backfilled with argon and charged with anhydrous1,4-dioxane (2.0 mL). The reaction was stirred under argon at 90° C. andmonitored by TLC. When the reaction was complete after 8 hours, thesolvent was removed in vacuo and the reaction crude was purified byflash column chromatography (2% methanol in dichloromethane) to afforddesired 2-(4-methylphenoxy)-6-(4-methoxy-benzylamino)-9-isopropylpurine(180 mg, 90%): ¹H NMR (400 MHz, CDCl₃) δ 1.53 (d, 6H, J=6.8 Hz), 2.37(s, 3H), 3.79 (s, 3H), 4.54 (br, 2H), 4.71 (m, 1H, J=6.8 Hz), 6.35 (br,1H), 6.81 (d, 2H, J=8.4 Hz), 7.10-7.18 (m, 6H), 7.65 (s, 1H); HRMS(MALDI-FTMS) [MH⁺] C₂₃H₂₆N₅O₂ 404.2081, found: 404.2080.

Purine N9 arylation via boronic acids/cupric acetate: A 20 mL glass vialequipped with a magnetic stir bar was charged with 2,6-dichloropurine(0.200 g, 1.06 mmol, 1.0 equiv), 4-methylphenylboronic acid (0.288 g,2.12 mmol, 2.0 equiv), anhydrous cupric acetate (0.384 g, 2.12 mmol, 2.0equiv.), 4 A activated molecular sieves (0.500 g), triethylamine (0.443mL, 3.18 mmol, 3.0 equiv.) and dichloromethane (5.0 mL). The reactionwas stirred under air at ambient temperature and monitored by TLC. Whenthe reaction was complete after 24 hours, it was filtered throughCelite, washed with methanol and purified by flash column chromatography(1% methanol in dichloromethane) to afford desired2,6-dichloro-9-(4-methylphenyl)-purine (0.136 g, 47%). ¹H NMR (400 MHz,CDCl₃) δ 2.47 (s, 3H), 7.41 (d, 2H, J=8.1 Hz), 7.54 (d, 2H, J=8.1 Hz),8.35 (s, 1H); HRMS (MALDI-FTMS) C₁₂H₈Cl₂N₄ [MH⁺] 279.0199, found:279.0208.

Example 2 General Procedure for Combinatorial Synthesis of HeterocycleLibraries

Reductive Amination for Synthesis of PAL-resin-bound amine (1). To asuspension of 4-formyl-3,5-dimethoxyphenoxymethyl functionalizedpolystyrene resin (PAL) (10.0 g, 11.3 mmol) in DMF (350 mL) was added aprimary amine (56.5 mmol), followed by addition of sodiumtriacetoxyborohydride (7.18 g, 33.9 mmol) and acetic acid (6.52 mL, 113mmol). The mixture was shaken gently at room temperature. Afterovernight the resin 1 was washed by methanol (300 mL×4) anddichloromethane (300 mL×4) and dried under vacuum. The completeconversion of PAL aldehyde to resin-bound amine was confirmed bydisappearance of the aldehyde stretch.

Resin Capture of Dichloroheterocycles (C). To a solution ofdichloro-heterocycle (S) (15.0 mmol) in n-butanol (200 mL) was addedPAL-resin-bound amine 1 (10.0 mmol), followed by addition ofdiisopropylethylamine (5.2 mL, 30.0 mmol). The suspension was heated to90° C. under argon. After 12 hours, the resin was washed by methanol(200 mL×4) and dichloromethane (200 mL×4) and dried under vacuum. Thecomplete conversion of secondary amine (PAL-amine) to tertiary amine wasconfirmed by bromophenol blue test.

Substitution of Remaining Chloro Group with Boronic Acids via SuzukiCoupling and Product Cleavage (P1). A 10 mL flame-dried Schlenk flaskwas charged with resin C (0.10 mmol, 1.0 equiv), arylboronic acid (0.50mmol, 5.0 equiv), Pd₂(dba)₃ (0.007 mmol, 0.07 equiv.), carbine ligand(0.014 mmol, 0.14 equiv.) and Cs₂CO₃ (0.60 mmol, 6.0 equiv.). TheSchlenk flask was evacuated and backfilled with argon and charged withanhydrous 1,4-dioxane (1.0 mL). The reaction was heated to 80° C. underargon. After 12 hours, the resin was washed by sodiumdiethyldithiocarbamate solution (0.05M in DMF, 1 mL×4), dichloromethane(1 mL×4) and methanol (1 mL×4) and dried under vacuum. The derivatizedresin was subsequently cleaved in CH₂Cl₂:TFA:Me₂S:H₂O/45:45:5:5/v:v:v:v(0.5 mL) for two hours. The solution was collected and the solvent wasremoved in vacuo to afford desired final product (P1).

Substitution of Remaining Chloro Group with Anllines or Amines viaPalladium-Catalyzed Reaction and Product Cleavage (P2). A 10 mLflame-dried Schlenk flask was charged with resin C (0.10 mmol, 1.0equiv), aniline or amine (0.50 mmol, 5.0 equiv), Pd₂(dba)₃ (0.007 mmol,0.07 equiv.), carbine ligand (0.014 mmol, 0.14 equiv.) and KO^(t)Bu(0.60 mmol, 6.0 equiv.). The Schlenk flask was evacuated and backfilledwith argon and charged with anhydrous 1,4-dioxane (1.0 mL). The reactionwas heated to 80° C. under argon. After 12 hours, the resin was washedby sodium diethyldithiocarbamate solution (0.05M in DMF, 1 mL×4),dichloromethane (1 mL×4) and methanol (1 mL×4) and dried under vacuum.The derivatized resin was subsequently cleaved inCH₂Cl₂:TFA:Me₂S:H₂O/45:45:5:5/v:v:v:v (0.5 mL) for two hours. Thesolution was collected and the solvent was removed in vacuo to afforddesired final product (P2).

Substitution of Remaining Chloro Group with Phenols viaPalladium-Catalyzed Reaction and Product Cleavage (P3). A 10 mLflame-dried Schlenk flask was charged with resin C (0.10 mmol, 1.0equiv), phenol (0.50 mmol, 5.0 equiv), Pd₂(dba)₃ (0.007 mmol, 0.07equiv.), phosphine ligand (0.028 mmol, 0.28equiv.) and K₃PO₄ (0.70 mmol,7.0 equiv.). The Schlenk flask was evacuated and backfilled with argonand charged with anhydrous toluene (1.0 mL). The reaction was heated to80° C. under argon. After 12 hours, the derivatized resin was washed bysodium diethyldithiocarbamate solution (0.05M in DMF, 1 mL×4),dichloromethane (1 mL×4) and methanol (1 mL×4) and dried under vacuum.The resin was subsequently cleaved inCH₂Cl₂:TFA:Me₂S:H₂O/45:45:5:5/v:v:v:v (0.5 mL) for two hours. Thesolution was collected and the solvent was removed in vacuo to afforddesired final product (P3).

Substitution of Remaining Chloro Group with Amines vianon-Palladium-Catalyzed Amination Reaction without Base and ProductCleavage (P4). The resin C (0.05 mmol) was suspended in the solution ofan amine (2M in n-butanol, 0.2 mL). After 12 hours heating at 80° C. ina sealed reaction vessel under argon, the resin was washed with methanol(1 mL×4) and dichloromethane (1 mL×4) and dried under vacuum. It wassubsequently cleaved using CH₂Cl₂:TFA:Me₂S:H₂O/45:45:5:5/v:v:v:v (0.3mL) to afford desired final product (P4) (>90% HPLC purity in average,80% purified yield).

Substitution of Remaining Chloro Group with Amines vianon-Palladium-Catalyzed Amination Reaction with KO^(t)Bu as Base andProduct Cleavage. To a suspension of resin C (0.05 mmol) in THF(anhydrous, 0.25 mL) was added an amine (0.25 mmol), followed byaddition of KO^(t)Bu solution (in THF, 1.0M, 0.25 mL, 0.25 mmol). After12 hours heating at 70° C. in a sealed reaction vessel under argon, theresin was washed with methanol (1 mL×4) and dichloromethane (1 mL×4) anddried under vacuum. It was subsequently cleaved usingCH₂Cl₂:TFA:Me₂S:H₂O/45:45:5:5/v:v:v:v (0.3 mL) to afford desired finalproduct (in average >85% HPLC purity, 80% purified yield). TABLE 1Validation of palladium catalyzed cross-coupling reactions forderivatizing resin-bound 2-chloro-6-aminopurine with boronic acids,anilines, amines and phenols. (Purities refer to HPLC purities, andyields refer to isolated yields by preparative TLC.)

C2 Substituents Retention Calculated Observed Purity & C2 SubstituentsRetention Calculated Observed Purity & Entry via boronic acids Time(min) [M] [MH⁺] Yields (%) Entry via anilines Time (min) [M] [MH⁺]Yields (%) B1

8.28 391.18 392.20 90 (84) An1

5.77^(a) 418.21 419.20 97 (90) B2

5.72 403.20 404.20 94 (85) An2

6.59 446.21 447.20 96 (91) B3

5.28 433.21 414.20 92 (85) An3

6.83 430.25 431.20 89 (81) B4

8.02 413.19 414.20 91 (82) An4

7.54 406.19 407.20 89 (80) B5

7.57 415.20 416.20 89 (80) An5

7.82 428.23 429.20 95 (88) B6

9.05 449.22 450.20 90 (85) An6

7.63 402.22 403.20 97 (91) C2 Substituents Retention Calculated ObservedPurity & C2 Substituents Retention Calculated Observed Purity & Entryvia amines Time (min) [M] [MH⁺] Yields (%) Entry via phenols Time (min)[M] [MH⁺] Yields (%) Am1

3.96 398.24 399.20 89 (83) P1

7.43 403.20 404.20 90 (82) Am2

4.31 437.25 438.30 97 (90) P2

7.53 403.20 404.20 91 (82) Am3

5.81 446.21 447.20 96 (91) P3

7.52 403.20 404.20 92 (81) Am4

5.07 431.24 432.20 91 (84) P4

7.59 439.20 440.20 88 (81) Am5

5.38 396.23 397.20 92 (84) P5

7.30 407.18 408.20 88 (81) Am6

8.71 525.25 526.20 98 (90) P6

8.03 465.22 466.20 92 (80)^(a)Using 17 minutes LC/MS method.

TABLE 2 Validation of resin-bound chloroheterocyclic scaffolds which canbe derivatized via Suzuki coupling reaction. (Purities refer to HPLCpurities, and yields refer to isolated yields by preparative TLC.)

Retention Calculated Observed Purity & Entry Scaffolds (R2) Time (min)[M] [MH⁺] Yield (%) 1

4.46 321.15 322.20 95 (90) 2

4.47 335.16 336.20 95 (91) 3

4.31 335.16 336.20 96 (91) 4

4.71 321.15 322.20 93 (89) 5

4.11 336.16 337.15 91 (85) 6

4.91 371.16 372.20 95 (90) 7

4.87 371.16 372.20 86 (79) 8

4.80 371.16 372.20 92 (85) 9

4.65 371.16 372.20 91 (82) 10

4.60 371.16 372.20 93 (83) 11

6.81 321.15 322.10 95 (85) 12

7.01 321.15 322.20 94 (84) 13

4.51 371.16 372.10 92 (85) 14

4.69 321.15 322.10 91 (84) 15

7.94 371.16 372.15 93 (84) 16

7.53^(a) 403.20 404.30 89 (80)^(a)Using 17 minutes LC/MS method.

TABLE 3 Validation of rein-bound chloroheterocyclic scaffolds which canbe derivatized via palladium catalyzed amination reaction. (Puritiesrefer to HPLC purities, and yields refer to isolated yields bypreparative TLC.)

Retention Calculated Observed Purity & Entry Scaffolds (R2) Time (min)[M] [MH⁺] Yield (%) 1

4.26 336.16 337.15 96 (90) 2

4.32 350.17 351.20 95 (91) 3

4.26 350.17 351.20 96 (90) 4

4.25 336.16 337.20 95 (90) 5

4.18 351.17 352.20 88 (82) 6

4.58 386.17 387.20 94 (89) 7

4.59 386.17 387.20 89 (78) 8

4.58 386.17 387.20 93 (86) 9

4.65 386.17 387.20 95 (89) 10

6.13 386.17 387.20 93 (85) 11

5.98 336.16 337.10 93 (86) 12

5.72 336.16 337.10 94 (89) 13

4.38 386.16 387.20 92 (84) 14

4.12 336.16 337.10 92 (87) 15

7.61 386.17 387.20 88 (81) 16

5.77^(a) 418.21 419.30 91 (85)^(a)Using 17 minutes LC/MS method.

TABLE 4 Validation of resin-bound chloroheterocyclic scaffolds which canbe derivatized via palladium catalyzed C—O bond formation reaction.(Purities refer to HPLC purities, and yields refer to isolated yields bypreparative TLC.)

Retention Calculated Observed Purity & Entry Scaffolds (R2) Time (min)[M] [MH⁺] Yield (%) 1

4.73 337.14 338.10 92 (86) 2

4.68 351.16 352.20 91 (85) 3

4.59 351.16 352.20 93 (88) 4

6.30 337.14 338.10 96 (88) 5

4.79 352.15 353.10 90 (83) 6

4.99 387.16 388.10 93 (89) 7

4.56 387.16 388.20 85 (78) 8

4.83 387.16 388.15 94 (85) 9

4.70 387.16 388.10 95 (89) 10

4.36 387.16 388.15 92 (88) 11

7.16 337.14 338.10 96 (88) 12

6.90 337.14 338.10 91 (84) 13

4.76 387.16 338.10 90 (83) 14

4.64 336.16 337.10 91 (86) 15

8.15 337.14 338.10 91 (83) 16

6.72^(a) 419.20 420.30 90 (85) ^(a)Using 17 minutes LC/MS method.

2-(2,4-dimethoxyphenyl)-6-(4-methoxybenzylamino)-9-isopropylpurine. ¹HNMR (400 MHz, CDCl₃) δ 1.59 (d, 6H, J=6.8 Hz), 3.79 (s, 3H), 3.84 (s,3H), 3.85 (s, 3H), 4.87-4.96 (m, 3H), 6.14 (br, 1H), 6.57-6.60 (m, 2H),6.85 (d, 2H, J=8.6 Hz), 7.34 (d, 2H, J=8.6 Hz), 7.73 (s, 1H), 7.78 (d,1H, J=8.2 Hz); HRMS (MALDI-FTMS) [MH⁺] C₂₄H₂₈N₅O₃ 434.2187, found:434.2168

2-(4-fluorophenyl)-6-(4-methoxybenzylamino)-9-isopropylpurine. ¹H NMR(400 MHz, CDCl₃) δ 1.61 (d, 6H, J=6.8 Hz), 3.81 (s, 3H), 4.87 (br, 2H),5.04 (m, 1H, J=6.8 Hz), 6.85 (d, 2H, J=8.4 Hz), 7.00 (d, 2H, J=8.8 Hz),7.17 (d, 2H, J=8.4 Hz), 7.73 (d, 2H, J=8.8 Hz), 8.38 (s, 1H); HRMS(MALDI-FTMS) [MH⁺] C₂₂H₂₃FN₅O 392.1881, found: 392.1885

2-(4-acetylphenyl)-6-(4-methoxybenzylamino)-9-isopropylpurine. ¹H NMR(400 MHz, CDCl₃) δ 1.79 (d, 6H, J=6.8 Hz), 2.52 (s, 3H), 3.81 (s, 3H),4.91 (d, 2H), 5.13 (m, 1H, J=6.8 Hz), 6.82 (d, 2H, J=8.5 Hz), 7.15 (d,2H, J=8.5 Hz), 7.88 (d, 2H, J=8.1 Hz), 7.97 (d, 2H, J=8.1Hz), 8.65 (s,1H); HRMS (MALDI-FTMS) [MH⁺] C₂₄H₂₆N₅O₂ 416.2081, found: 416.2099

2-(2-methoxyphenyl)-6-(4-methoxybenzylamino)-9-isopropylpurine. ¹H NMR(400 MHz, CDCl₃) δ 1.60 (d, 6H, J=6.8 Hz), 3.79 (s, 3H), 3.85 (s, 3H),4.87 (d, 2H), 4.92 (m, 1H, J=6.8 Hz), 5.99 (br, 1H), 6.86 (d, 2H, J=8.5Hz), 7.01-7.06 (m, 2H), 7.35 (m, 3H), 7.72 (d, 1H, J=7.2 Hz), 7.79 (s,1H); HRMS (MALDI-FTMS) [MH⁺] C₂₃H₂₆N₅O₂ 404.2081, found: 404.2056

2-(4-methoxyphenylamino)-6-(4-methoxybenzylamino)-9-isopropylpurine: ¹HNMR (500 MHz, CDCl₃) δ 1.54 (d, 6H, J=6.6 Hz), 3.76 (s, 3H), 3.78 (s,3H), 4.66 (m, 1H, J=6.6 Hz), 4.72 (br, 2H), 6.06 (br, 1H), 6.60 (br,1H), 6.82 (d, 2H, J=13 Hz, 6.84 (d, 2H, J=13 Hz), 7.09 (s, 1H), 7.26 (d,2H, J=8.8 Hz), 7.42 (s, 1H), 7.56 (d, 2H, J=8.8 Hz); HRMS (MALDI-FTMS)[MH⁺] C₂₃H₂₇N₆O₂ 419.2195, found: 419.2209

2-(2-fluorophenylamino)-6-(4-methoxybenzylarnino)-9-isopropylpurine: ¹HNMR (400 MHz, CDCl₃) δ 1.58 (d, 6H, J=6.8 Hz), 3.78 (s, 3H), 4.69 (m,1H, J=6.8 Hz), 4.76 (br, 2H), 6.34 (br, 1H), 6.85 (d, 2H, J=8.4 Hz),7.04-7.11 (m, 2H), 7.14 (d, 1H, J=2.8 Hz), 7.30 (d, 2H, J=8.4 Hz), 7.50(s, 1H), 8.62 (t, 1H, J=8.4 Hz); HRMS (MALDI-FTMS) [MH⁺] C₂₂H₂₄FN₆O407.1990, found: 407.1996.

2-(1,4-benzodioxan-6-amino)-6-(4-methoxybenzylamino)-9-isopropylpurine:¹H NMR (400 MHz, CDCl₃) δ 1.56 (d, 6H, J=6.8 Hz), 3.78 (s, 3H), 4.24 (m,4H), 4.70 (m, 1H, J=6.8 Hz), 4.72 (br, 2H), 6.14 (br, 1H), 6.77 (d, 1H,J=8.7 Hz), 6.85 (m, 3H), 6.99 (m, 1H), 7.29 (d, 2H, J=8.5 Hz), 7.44 (d,1H, J=2.3 Hz), 7.49 (s, 1H); HRMS (MALDI-FTMS) [MH⁺] C₂₄H₂₇N₆O₃447.2139, found: 447.2134

2-(indan-5-amino)-6-(4-methoxybenzylamino)-9-isopropylpurine: ¹H NMR(400 MHz, CDCl₃) δ 1.57 (d, 6H, J=6.8 Hz), 2.06 (m, 2H), 2.86 (m, 4H),3.78 (s, 3H), 4.69 (m, 1H, J=6.8 Hz), 4.75 (br, 2H), 6.09 (br, 1H), 6.85(d, 2H, J=8.5 Hz), 6.92 (s, 1H), 7.13 (d, 1H, J=8.1 Hz), 7.29 (d, 2H,J=8.5 Hz), 7.40 (d, 1H, J=8.0 Hz), 7.50 (s, 1H), 7.60 (s, 1H); HRMS(MALDI-FTMS) [MH⁺] C₂₅H₂₉N₆O 429.2397, found: 429.2417

2-(2,4,6-tri-methylphenylamino)-6-(4-methoxybenzylamino)-9-isopropylpurine:¹H NMR (400 MHz, CDCl₃) δ 1.47 (d, 6H, J=6.8 Hz), 2.22 (s, 6H), 2.31 (s,3H), 3.78 (s, 3H), 4.52 (br, 2H), 4.60 (m, 1H, J=6.8 Hz), 5.86 (br, 1H),6.11 (br 1H), 6.77 (d, 2H, J=8.4 Hz), 6.93 (s, 2H), 7.10 (d, 2H,J=7.5Hz), 7.49 (s, 1H); HRMS (MALDI-FTMS) [MH⁺] C₂₅H₃₁N₆O 431.2554,found: 431.2569

2-(N-methylphenylamino)-6-(4-methoxybenzylamino)-9-isopropylpurine: ¹HNMR (400 MHz, CDCl₃) δ 1.52 (d, 6H, J=6.8 Hz), 3.57 (s, 3H), 3.77 (s,3H), 4.54 (br, 2H), 4.62 (m, 1H, J=6.8 Hz), 5.92 (br, 1H), 6.79 (d, 2H,J=8.5 Hz), 7.10 (d, 1H, J=7.3 Hz), 7.15 (d, 2H, J=8.5 Hz), 7.32 (m, 2H),7.38 (d, 2H, J=7.7 Hz), 7.48 (s, 1H); HRMS (MALDI-FTMS) [MH⁺] C₂₃H₂₇N₆O403.2241, found: 403.2249

2-(4-methylphenoxy)-6-(4-methoxybenzylamino)-9-isopropylpurine. ¹H NMR(400 MHz, CDCl₃) δ 1.53 (d, 6H, J=6.8 Hz), 2.37 (s, 3H), 3.79 (s, 3H),4.54 (br, 2H), 4.71 (m, 1H, J=6.8 Hz), 6.35 (br, 1H), 6.81 (d, 2H, J=8.4Hz), 7.10-7.18 (m, 6H), 7.65 (s, 1H); HRMS (MALDI-FTMS) [MH⁺] C₂₃H₂₆N₅O₂404.2081, found: 404.2080

2-(3-methylphenoxy)-6-(4-methoxybenzylamino)-9-isopropylpurine. ¹H NMR(400 MHz, CDCl₃) δ 1.53 (d, 6H, J=6.8 Hz), 2.37 (s, 3H), 3.78 (s, 3H),4.52 (br, 2H), 4.71 (m, 1H, J=6.8 Hz), 6.62 (br, 1H), 6.81 (d, 2H, J=8.4Hz), 7.00-7.05 (m, 3H), 7.14 (d, 2H, J=7.7 Hz), 7.25 (d, 1H, J=7.8 Hz),7.66 (s, 1H); HRMS (MALDI-FTMS) [MH⁺] C₂₃H₂₆N₅O₂ 404.2081, found:404.2092

2-(2-methylphenoxy)-6-(4-methoxybenzylamino)-9-isopropylpurine. ¹H NMR(400 MHz, CDCl₃) δ 1.52 (d, 6H, J=6.8 Hz), 2.20 (s, 3H), 3.78 (s, 3H),4.42 (br, 2H), 4.71 (m, 1H, J=6.8 Hz), 6.63 (br, 1H), 6.77 (d, 2H, J=8.4Hz), 7.04 (m, 2H), 7.11 (d, 1H, J=7.8 Hz), 7.15 (d, 1H, J=7.4 Hz), 7.21(d, 1H, J=7.6 Hz), 7.25 (1H), 7.65 (s, 1H); HRMS (MALDI-FTMS) [MH⁺]C₂₃H₂₆N₅O₂ 404.2081, found: 404.2087

1H NMR (500 MHz, d6-DMSO) δ: d 0.85 (d, 6H, 7.1 Hz), 1.44 (d, 6H, 7.1Hz), 1.93 (m, 1H), 3.31 (s, 2H), 3.46 (d, 2H, 5.3 Hz), 3.69 (s, 3H),3.79 (m, 1H), 4.49 (m, 3H), 5.75 (s, 1H), 6.83 (d, 2H, J=8.7 Hz), 7.27(d, 2H, J=8.7 Hz), 7.75 (s, 1H); HRMS calc'd for C₂₁H₃₀N₆O₂ [MH⁺]399.2508, found: 399.2510.

1H NMR (400 MHz, CDCl₃) δ: 1.61 (d, 6H, J=6.8 Hz), 1.92 (m, 2H), 2.10(m, 2H), 2.52 (t, 2H, J=6.3 Hz), 3.44-3.56 (m, 6H), 3.80 (s, 3H), 4.81(b, 3H)), 6.88 (d, 2H, J=7.9 Hz), 7.32 (d, 2H), 8.08 (s, 1H); MS (ES)calc'd for [MH⁺] C₂₃H₃₂N₇O₂ 438.26, found 438.30

2-(4-methoxybenzylamino)-6-(3-methoxyphenyl)-pyrazine. ¹H NMR (400 MHz,CDCl₃) δ 3.82 (s, 3H), 3.85 (s, 3H), 4.99 (br, 2H), 6.91-6.99 (m, 4H),7.16 (d, 2H, J=8.8 Hz), 7.43-7.56 (m, 4H); MS (ES) calc'd for [MH⁺]C₁₉H₂₀N₃O₂ 322.16, found 322.20

2-(4-methoxybenzylamino)-3-(3-methoxyphenyl)-quinoxaline. ¹H NMR (400MHz, CDCl₃) δ 3.79 (s, 3H), 3.84 (s, 3H), 4.95 (br, 2H), 5.86 (br, 1H),6.87 (d, 2H, J=8.5 Hz), 7.05 (m, 1H), 7.25 (2H), 7.31 (d, 2H, J=8.4 Hz),7.36 (m, 3H), 7.66 (m, 1H), 7.96 (d, 1H, J=8.1 Hz); MS (ES) calc'd for[MH⁺] C₂₃H₂₂N₃O₂ 372.17, found 372.20

2-(3-methoxyphenyl)-4-(4-methoxybenzylamino)-5-methyl-quinoxaline. ¹HNMR (400 MHz, CDCl₃) δ 2.15 (s, 3H), 3.89 (s, 3H), 3.98 (s, 3H), 4.87 (d2H, J=5.4 Hz), 5.83 (br, 1H), 6.93 (d, 2H, J=8.6 Hz), 7.15 (dd, 1H),7.33 (d, 2H, J=8.6 Hz), 7.45 (t, 1H, J=8.0 Hz), 8.14 (2H), 8.20 (d, 1H,J=8.3 Hz); MS (ES) calc'd for [MH⁺] C₂₀H₂₂N₃O₂ 336.17, found 336.20

4-(4-methoxybenzylamino)-7-(3-methoxyphenyl)-quinazoline. ¹H NMR (400MHz, CDCl₃) δ 3.75 (s, 3H), 3.81 (s, 3H), 4.90 (br, 2H), 6.82 (m, 4H),6.97 (2H), 7.47 (m, 4H), 8.21-8.49 (m, 3H); MS (ES) calc'd for [MH⁺]C₂₃H₂₂N₃O₂ 372.17, found 372.20

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto included within the spirit and purview of this application and areconsidered within the scope of the appended claims. All publications,patents, and patent applications cited herein are hereby incorporated byreference in their entirety for all purposes.

1. A compound having the following Formula:

wherein R is selected from the group consisting of a 5- or 6-memberedheteroaryl and a 9- or 10-membered 6,5- or 6,6-fused heteroaryl,containing from 1-4 nitrogen atoms, optionally substituted with 1-2groups independently selected from the group consisting of hydrogen,C₁₋₆alkyl, aryl, C₁₋₆alkylaryl, C₃₋₈cycloalkyl, heterocycle, heteroaryl,C₁₋₆alkylhydroxy, C₁₋₆alkoxy and NR⁴R⁴; R¹ is a member selected from thegroup consisting of phenyl and benzyl, substituted on the aromatic ringwith from 1-4 substituents independently selected from the groupconsisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylhydroxy, C₁₋₆alkylamine,C₁₋₆aminoalkyl, halo and heterocycle; L is selected from the groupconsisting of —O—, —NR²— and a bond; each R² is independently a memberselected from the group consisting of hydrogen and C₁₋₄alkyl; R³ isindependently a member selected from the group consisting of hydrogen,optionally substituted alkyl, optionally substituted heteroalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocycloalkyl, halogen and alkoxy groups; orR² and R³ taken together form a 3-8 membered heterocyclic ringcontaining from 1-2 heteroatoms selected from the group consisting of Nand O, optionally substituted with 1-2 members independently selectedfrom the group consisting of C₁₋₄alkyl, C₁₋₄alkylhydroxy, C₁₋₄alkoxy andC₁₋₄alkylamine; R⁴, if present, is a member selected from the groupconsisting of optionally substituted alkyl, optionally substitutedheteroalkyl and acyl groups; and all pharmaceutically acceptable salts,hydrates, solvates, isomers and prodrugs thereof.
 2. A compound of claim1, wherein R is a 6-membered aromatic ring containing 2 nitrogen atoms.3. A compound of claim 1, wherein R is a 6,5-fused aromatic ringcontaining from 1-4 nitrogen atoms.
 4. A compound of claim 1, wherein Ris a 6,6-fused aromatic ring containing from 1-4 nitrogen atoms.
 5. Acompound of claim 1, wherein R is a member selected from the groupconsisting of:


6. A compound of claim 1, wherein R is a member selected from the groupconsisting of:


7. A compound of claim 1, wherein R is a member selected from the groupconsisting of:


8. A compound of claim 1, wherein R is the following structure:


9. A compound of claim 1, wherein: R is a 2,6,9-substituted purine,substituted with a member selected from the group consisting of:

R¹ is a phenyl substituted with morpholine; L-R³ is a member selectedfrom the group consisting of-.

R⁴ is not present.
 10. A compound of claim 1, wherein R¹ is


11. A compound of claim 1, wherein L and R³ taken together are selectedfrom the group consisting of:


12. A compound of claim 1, wherein R⁴, when present, is isopropyl.
 13. Acompound of claim 1, wherein R² is H or Me.
 14. A compound of claim 1,selected from the group consisting of:


15. A compound of claim 1, selected from the group consisting of:


16. A pharmaceutical composition comprising a compound according toclaim 1, and a pharmaceutically acceptable carrier.